Abstract
Purpose :
Virus-associated diseases are a complex interaction between viral replication and immune responses. As obligate intracellular pathogens, viruses are dependent on cellular metabolism. In metabolic arrays, viral infection highly upregulated TPH2, the serotonin(5HT) synthesis rate-limiting enzyme. 5HT has recently been associated as a pro-inflammatory mediator; however, the role of 5HT in viral replication or in virus-associated ocular disease has not been defined. We hypothesized that viral-mediated serotonin production promotes viral replication and as a consequence contributes to inflammation-associated ocular disease.
Methods :
Expression of serotonin genes was assessed by PCR, western and IFA for two ocular viral pathogens, Adenovirus and Herpes Simplex 1. Concomitant 5HT synthesis was determined by ELISA. Serotonin’s effect on viral yield was evaluated following serotonin addition or pharmacological inhibition (LX1031) of TPH. HSV-1 McKrae ocularly infected NZW rabbits were clinically scored daily. At sacrifice, aqueous humor 5HT levels were analyzed and correlated with assessed clinical disease parameters by Pearson’s and Spearman’s. The potential therapeutic effects of the 5HT2A receptor agonist, R-DOI, was determined in a herpetic eye model with or without TFT antiviral treatment.
Results :
Expression of critical 5HT-associated genes TPH1, TPH2, DDC, and SERT were increased following viral infection. Concordantly, infected cells upregulated 5HT production and its intracellular transport. Addition of 5HT increased HSV yield, while TPH inhibition reduced yield. In agreement with in vitro studies, HSV ocularly-infected rabbits had significantly higher aqueous humor 5HT that strongly positively correlated with multiple ocular clinical disease scores. Modulation of the serotonin 5HT2A receptor with topical R-DOI treatment reduced viral replication and reactivation, intraocular pressure, neurological disease, and inflammation-associated clinical parameters.
Conclusions :
Virus-induced 5HT production underlies subsequent development of chronic inflammation-associated ocular disease processes, including hypertension, inflammation, neovascularization, vascular leakage and fibrosis. Modulation of these disease processes through the serotonin 5HT2A receptor represents a potential novel therapeutic target for numerous ocular inflammatory diseases.
This is a 2020 ARVO Annual Meeting abstract.